Process for the preparation of a 3(2H)-pyridazinone-4- substituted amino 5-chloro derivative

ABSTRACT

The invention relates to novel processes for the preparation of 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propylamino-3(2H) pyridazinone of formula (I) and the pharmaceutically acceptable acid addition salts thereof. An important feature of the invention is using 3,4,5-trichloropyridazone as starting substance of the synthesis.

The invention relates to a process for the preparation of5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methyl-amino]-propylamino}-3(2H)-pyridazinoneof the formula (I).

The British patent specification No. 2 262 526 provides new3(2H)-pyridazinone-4-substituted amino-5-halo derivatives which possessvaluable antiarrhythmic properties and prevent ventricular and auricularfibrillations. The5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methyl-amino]-propylamino}-3(2H)-pyridazinoneof formula (I) is described in the above-mentioned British patentspecification.

According to the British patent specification No. 2 262 526 the compoundof formula (I) is prepared by reacting 4,5-di-chloro-3(2H)-pyridazinoneof formula (XI)

with the amine of formula (X).

The drawback of the process resides in the fact that a mixture of thedesired compound of formula (I) and the regioisomer thereof of formula(IA)

is obtained, wherein the main component is the undesired isomer offormula (IA), while the desired compound of formula (I) is present onlyas a side-product, in an amount of a few %. Only by expensive andcumbersome column chromatography can the compound of formula (I) beseparated and isolated in a pure state from the thus-obtained mixture. Afurther disadvantage of the method is that a considerable (2.5-3-fold)molar excess of the expensive amino component of formula (X) obtained ina multi-step reaction is applied, which renders the method lesseconomical.

The present invention aims at providing a more regio-selective methodfor the preparation of5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propyl-amino}-3(2H)-pyridazinoneof the formula (I), which is devoid of the drawbacks of the hithertoknown processes.

It has been found that the above aim can be achieved by producing the5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propylamino}-3(2H)-pyridazinoneof formula (I) and pharmaceutically acceptable acid addition saltsthereof according to the method of the invention, which comprises

a₁) reacting a compound of the general formula (II),

wherein X stands for a leaving group, with N-methyl-homoveratryl amineof the formula (VI);

or

a₂) reacting a compound of the general formula (III),

wherein R stands for lower alkanoyl, aroyl or aryl-(lower alkanoyl),with an agent containing a leaving group of the formula X and reactingthe thus-obtained compound of the general formula (II) with the compoundof formula (VI); or

a₃) reacting 4-(3-hydroxypropylamino)-3,5-dichloro-pyridazine of theformula (IV)

with an agent suitable for introducing a group of the formula R,reacting the thus-obtained compound of general formula (III) with anagent containing a leaving group of the formula X and reacting thethus-obtained compound of general formula (II) with the compound offormula (VI); or

a₄) reacting 3,4,5-trichloropyridazine of the formula (V)

with 3-amino-1-propanol, reacting the thus-obtained compound of formula(IV) with an agent suitable for introducing a group of the formula R,reacting the thus-obtained compound of general formula (III) with anagent containing a leaving group of the formula X and reacting thethus-obtained compound of general formula (II) with a compound of theformula (VI); or

b₁) removing the group of the formula R (wherein R is as stated above)from a compound of general formula (IX);

or

b₂) reacting the compound of formula (VIII)

with an agent suitable for introducing a group of the formula R andremoving the group of formula R from the thus-obtained compound ofgeneral formula (IX); or

b₃) reacting a compound of the general formula (VII),

wherein X is as stated above, with a compound of the formula (VI),reacting the thus-obtained compound of formula (VIII) with an agentsuitable for introducing a group of the formula R, and removing thegroup of the formula R from the thus-obtained compound of generalformula (IX); or

b₄) reacting the compound of formula (IV) with an agent containing aleaving group of the formula X, reacting the thus-obtained compound ofgeneral formula (VII) with the compound of formula (VI), reacting thethus-obtained compound of general formula (VIII) with an agent suitablefor introducing a group of the formula R and removing the group of theformula R from the thus-obtained compound of general formula (IX);

and, if desired, converting the thus-obtained compound of formula (I)into an acid addition salt thereof.

The invention is based on the discovery that the regio-selectivity ofthe reaction can be improved considerably when using3,4,5-trichloropyridazine of the formula (V) as starting substance. Whenreacting the compound of formula (V) with 3-amino-1-propanol anapproximately 1:1 mixture of the desired compound of formula (IV) andthe regioisomer thereof of formula (IVA)

is obtained. A further advantage of the application of the compound offormula (V) as starting substance resides in the fact that the isomersof formulae (IV) and (IVA) can readily be separated by crystallization,and thus the expensive column chromatography cumbersome on an industrialscale can be eliminated. A further advantage of the process according tothe invention is that the regioisomers are separated at the beginning ofthe synthesis, when the first intermediate is formed, so the furtherreaction steps and the closing step are carried out with the applicationof only one regioisomer. Thus the desired product can be separated fromthe reaction mixture with a reduced loss and in a higher purity comparedto the hitherto known processes. It was not aforeseen that theregioisomers of formulae (IV) and (IVA) can be separated so simply, bycrystallization, and converted to the compounds of general formulae (II)and (III) with such a high yield.

In the first step of variant a) according to the invention3,4,5-trichloropyridazine of the formula (V) is reacted with3-amino-l-propanol. The reaction is carried out in an organic solvent.As reaction medium preferably lower alkanols (such as methanol, ethanol,n-propanol, preferably ethanol) or dipolar aprotic solvents (such asacetonitrile or dimethylformamide) are used. The reaction is carried outin the presence of an acid binding agent. For this purpose inorganicacid binding agents (e.g. alkali carbonates, such as sodium carbonate orpotassium carbonate, alkali hydrogen carbonates, such as sodium hydrogencarbonate or potassium hydrogen carbonate), or organic acid bindingagents (e.g. amines, such as triethylamine or diethyl isopropyl amine)can be used. According to a preferable embodiment of the processaccording to the present invention the excess of 3-amino-1-propanol usedas reactant may serve as solvent. The reaction can be performed at atemperature between 50° C. and 100° C., preferably at the boiling pointof the reaction mixture.

When the reaction has been accomplished the reaction mixture ispreferably worked up by removing the solvent and treating the residuewith distilled water or with a 5 to 15% sodium chloride solution. Thusthe two isomers can readily be separated, as the precipitate rich in theundesired isomer of the formula (IVA) can be isolated easily, byfiltration, from the aqueous solution rich in the desired isomer of theformula (IV). If desired, both isomers can be subjected to furtherpurification. The isomer of formula (IVA) can be purified byre-crystallization from an alcohol, while the compound of formula (IV)can be purified by extraction carried out with an organic solvent (e.g.ethyl acetate or halogenated hydrocarbons, such as dichloroethane orchloroform) followed by drying and evaporating the extract andre-crystallizing the residue from diethyl ether.

In the second reaction step of variant a) the thus-obtained compound offormula (IV) is reacted with an agent suitable for introducing a groupof the formula R, wherein R is a lower alkanoyl (e.g acetyl, propionylor butyryl), aroyl (e.g. benzoyl optionally carrying a substituentselected from the group consisting of halogen, alkoxy andtrifluoro-methyl) or aryl-(lower alkanoyl) (e.g. phenylacetyl).Compounds of the general formula (III) containing an acetyl group in theplace of R can be prepared and used advantageously in the synthesis.

The starting compound of formula (IV) applied for the second step of thesynthesis may be either purified or unpurified. Surprisingly it has beenfound that when the compound of the formula (IV) is unpurified, thecompound of general formula (III) is obtained in at least such a highpurity and good yield than when starting from a purified compound of theformula (IV). If a compound of the general formula (III) containingacetyl in the place of R is prepared, the compound of formula (IV) isreacted with acetic acid, in the presence of an excess of sodiumacetate. As reaction medium preferably glacial acetic acid is used andthe sodium acetate is applied in a 2.5 to 3-fold molar excess. Thereaction may be carried out at a temperature between 80° C. and 120° C.,it is performed preferably at a temperature of about 100° C. Thereaction mixture can be worked up by extraction carried out with anorganic solvent (preferably dichloromethane) followed by drying andevaporating the organic phase. The product is purified byrecrystallization from an alkanol (preferably methanol).

The compound of formula (III) obtained in the third reaction step ofvariant a) is reacted with an agent containing a leaving group of theformula X, wherein X represents preferably a halogen atom (e.g. chlorineor bromine) or an alkylsulfonyloxy (such as benzenesulfonyl-oxy,p-tolylsulfonyloxy or p-bromophenylsulfonyloxy) group.

It is preferable to carry out the reaction via an intermediate of thegeneral formula (II), wherein X stands for bromine. In this case thecompound of general formula (III) is reacted with an aqueous hydrogenbromide solution. It is preferable to use a 48% aqueous hydrogen bromidesolution. Thus the group of formula R can be removed from the amino andhydroxy groups in excellent yields an in a single reaction step, and4-(3-bromopropylamino)-5-chloro-3(2H)-pyridazinone of the formula (II)is obtained. The reaction is carried out at a temperature between 80° C.and 110° C., preferably at about 98° C. The reaction mixture can beworked up readily. The separated product is isolated by filtration orcentrifugation and optionally crystallized from an alcohol. The compoundof general formula (II) containing a bromine atom in the place of X is ahighly preferable intermediate, because the bromine atom is a leavinggroup easy to be split off.

In the next reaction step of variant a) the compound of general formula(II) is reacted with N-methyl-N-[2-(3,4-dimethylphenyl)-ethyl]-amine(N-methyl-homoveratrylamine). The reaction is carried out in a solvent,in the presence of an acid binding agent. As reaction medium preferablydipolar aprotic solvents (such as acetone, acetonitrile ordimethyl-formamide) may be used. As acid binding agent inorganiccompounds (e.g. alkali carbonates, such as sodium carbonate or potassiumcarbonate, or alkali hydrogen carbonates, such as sodium hydrogencarbonate or potassium hydrogen carbonate) or organic compounds (e.g.triethyl-amine or dipropylethylamine) may be used. The reaction iscarried out at a temperature between 40° C. and the boiling point of thereaction mixture. One can also proceed by applying excess amine of theformula (VI) which may serve as acid binding agent.

The reaction mixture can be worked up by known methods, e.g it isevaporated and the residue is poured into water, extracted with anorganic solvent (such as dichloromethane or ethyl acetate), the organicextract is filtered, dried and purified by crystallization.

In the first step of variant b) of the process according to theinvention the compound of formula (IV) is reacted with an agentcontaining a leaving group of the formula X. When preparing compounds ofthe general formula (VII) containing bromine or chlorine in the place ofX the compound of formula (IV) is reacted with thionyl bromide orphosphorus oxybromide, or thionyl chloride or phosphorus oxychloriderespectively. The reaction is carried out at a temperature between −10°C. and 100° C., in an inert organic solvent. As solvent halogenatedhydrocarbons (such as dichloro-methane, dichloroethane, chloroform,trichloroethylene, chloro-benzene or carbon tetrachloride), dipolaraprotic solvents (such as acetonitrile) or aromatic solvents (such asbenzene or toluene) may be used. The compound of general formula (VII),wherein X stands for bromine, can be prepared from the compound offormula (IV) with aqueous hydrogen bromide in organic acids (e.g. aceticor formic acid), at a temperature between 20° C. and 150° C. as well.

The compounds of general formula (VII), wherein X stands foralkylsulfonyloxy or arylsulfonyloxy, can be prepared by reacting thecompound of formula (IV) with an appropriate sulfonic chloride in aninert solvent, in the presence of an acid binding agent, at atemperature between −20° C. and 60° C. As reaction medium halogenatedhydrocarbons (such as trichloromethane, dichloroethane, chloroform,trichloroethylene, chlorobenzene or carbon tetrachloride) or aromatichydrocarbons (e.g. benzene or toluene) may be applied. As acid bindingagent organic bases (e.g. triethylamine or pyridine) can be used.

In the next reaction step of variant b) the thus-obtained compound ofgeneral formula (VII) is reacted with an amine of the formula (VI). Thereaction is preferably carried out in a dipolar aprotic solvent (such asacetone, aceco-nitrile, dimethylformamide) in the presence of an acidbinding agent. As acid binding agent inorganic compounds (such aspotassium carbonate or potassium hydrogen carbonate) or organiccompounds (such as triethylamine) can be used. An excess of the amine ofthe formula (VI) may also serve as acid binding agent. The reaction iscarried out at a temperature between 10° C. and the boiling point of thereaction mixture. The reaction mixture can be worked up by knownmethods, e.g. the solvent is removed, the residue is poured onto water,extracted with an organic solvent (such as dichloromethane or diethylacetate) and the extract is filtered and dried.

The thus-obtained compound of general formula (VIII) is then reactedwith an agent suitable for introducing the group of formula R. Thereaction is carried out as specified above in connection with theconversion of the compound of formula (IV) into the compound of formula(III). Preferably compounds of the general formula (IX) containing anacetyl group in the place of R are prepared. For this purpose it ispreferable to carry out the reaction of the compound of formula (VIII)in glacial acetic acid, in the presence of anhydrous sodium acetateapplied in a 1 to 5-fold molar excess, at a temperature between 40° C.and 140° C., preferably between 80° C. and 120° C.

In the last reaction step of variant b) the group of formula R isremoved from the compound of general formula (IX). The reaction ispreferably carried out with hydrogen bromide, particularly with 48%aqueous hydrogen bromide.

The thus-obtained compound of general formula (I) is optionallyconverted into a pharmaceutically acceptable acid addition salt. Thesalt formation is carried out by methods known per se, with acidsgenerally used in the pharmacological industry. Both inorganic acids(such as hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuricacid etc.) and organic acids (such as maleic, fumaric, citric, malic,lactic, succinic acid etc.) may be applied. It is preferable to preparethe acid addition salt of the compound of formula (I) formed withhydrogen chloride or fumaric acid.

The compound of formula (V) can be prepared by reacting4,5-dichloro-3(2H)-pyridazinone with phosphorous oxychloride [T.Kuraishi: Pharm. Bull. (Tokyo) 4, 497 (1956)].

The advantages of the process according to the invention compared to thehitherto known processes are as follows:

the reaction is significantly more regioselective than the knownprocesses,

the desired isomer can be separated from the obtained regioisomer by asimple crystallization, thus the complicated column chromatographycumbersome on an industrial scale can be eliminated,

the regioisomers are separated at an early stage of the synthesis,consequently only one regioisomer is used in the further steps of theprocess,

the reaction steps can be carried out in high yields (e.g. thepreparation of the compounds of the formulae (II) and (III)), theend-product of the formula (I) is obtained in a high yield and with highpurity.

The invention is further illustrated by the following Examples ofnon-limiting character:

EXAMPLE 1 4-(3-hydroxypropylamino)-3,5-dichloropyridazine (IV) and5-(3-hydroxypropylamino-3.4-dichloropyridazine (IVA)

47.93 g (0.261 mole) of 3,4,5-trichloro-pyridazine are dissolved inethanol and 49.7 ml (r=0.982 g/cm³, 0.65 mole) of 3-amino-1-propanol areadded to it under stirring. The solution is heated to boiling, boiledfor 30 minutes and a sample is taken for TLC (eluent: a 10:10:0.5mixture of ethyl acetate:acetone:triethylamine, R_(f) values: (XI)=0.90,(IV)=0.48, (IVA)=0.32, contamination of unknown stucture=0.75). Thereaction takes place generally within 30 minutes and 1 hour, the wholeamount of the starting substance is used up. The reaction mixture isthen evaporated, 13 g of sodium chloride are dissolved in distilledwater and the thus-obtained solution is added to the evaporated mixtureunder stirring. The reaction mixture is allowed to stand in arefrigerator overnight at 5° C. The separated crystals are washed with10 to 12 ml of cold distilled water and the precipitate is dried. Thus27.7 g (47.7%) of crude product (IVA) are obtained. M.p.: 150-153° C.After recrystallization from methanol the melting point rises to157-158° C. The physical characteristics will be specified later.

The aqueous mother liquor is extracted 5 times with 200 cm³ each ofethyl acetate, dried over hot magnesium sulfate, filtered on activatedcarbon and evaporated to dry. The bulk of the residual crude product isthe compound of formula (IV).

Yield of the crude product: 28.02 g (48.32%), according to HPLC analysisit contains 7 to 8% of (IVA) and 1 to 2% of contamination of unknownstructure. The crude product is purified by recrystallization from colddiethyl ether in the following way: 300 ml of diethyl ether are added toit in 5 portions and the oily product is stirred at room temperature.The ether solution is decanted on every occasion and fresh ether isused. The ether solutions are combined, evaporated to a volume of 100 mland the separated crystals are filtered off. Thus 15.6 g (26%) ofcompound of the formula (IV) are obtained. M.p.: 65-66° C. According toMPLC analysis carried out after purification (IVA) <3.0% and (IV)>97%.For the elaboration of the HPLC method small amounts of standards havebeen prepared by column chromatography. HPLC method:

Column: Ultrasphere SI 3 mm. 75 cm×4.6 mm.

Eluent: cyclohexane:ethyl acetate (1:1).

Flow rate: 1.0 ml/min.

Detection: UV 254 nm.

Injected volume: 20 ml (0.8% dilution).

Retention times: 5.13 for compound (IV) and 13.46 minutes for compound(IVA).

The Physico-chemical Characteristics of4-(3-hydroxypropyl-amino)-3,5-dichloropyridazine (IV)

M.p.: 65-66° C.

TLC: ethyl acetate:triethylamine=20:0.5

R_(f)=0.36

Analysis for the formula C₇H₉Cl₂NO₃ (222.08): C H Cl N Calculated:37.86% 4.09% 31.93% 18.92% Found: 37.62 4.12% 31.71% 18.67% IR (KRr) νcm⁻¹: 3249, 2947, 1591, 1454, 1390, 1353, 1212, 1177, 1124, 1075, 1037,908, 683, 522, 460.

¹H-NMR (DMSO): δ 8.70 [s, (1H) pyridazine C-6 ], 6.8 [t, (1H) 4-NH], 4.7[t, (1H) OH], 3.74 [qa, (2H) N—CH ₂], 3.5 [qa, (2H) CH₂—O—] 1.73 [m,(2H) C—CH₂—C].

¹³CNMR (DMSO) δ ppm: 150.8, 116.0, 140.1, 114.7 (pyridazine carbonatoms), (60 C—OH), (43.6 NH—C), (31.9 C—CH₂—C).

Physico-chemical Characteristics of the5-(3-hydroxypropyl-amino)-3.4-dichloropyridazine (IVA)

M.p.: 157-158° C.

TLC: ethyl acetate:triethylamine=20:0.5

R_(f)=0.16

Analysis for the formula C₇H₉Cl₂N₃O (222.08): C H Cl N Calculated:37.86% 4.09% 31.93% 18.92% Found: 37.68 4.11% 31.77% 18.73% IR (KBr) νcm⁻¹: 3269, 2935, 1568, 1334, 1283, 1224, 1139, 1070, 1043, 861, 830,795, 661, 540, 514.

¹H-NMR (DMSO): δ ppm: 8.73 [s,(1H) pyridazine C-6], 7.59 [t,(1H) 5-NH],4.66 [t,(1H) OH], 3.4-3.6 [m,(4H) CH₂-X X=heteroatom], 1.73 [m,(2H)C—CH₂C].

The stereoscopic vicinity of the NH proton at position 5 and thepyridazine proton at position 6 has been proved by a DNOE experiment.

¹³CNMR (DMSO) δ ppm: 152.1, 143.7, 137.2, 114.4 (pyridazine carbonatoms), (58.4 C—OH), (39.9 C—NH), (31.4 C—CH₂—C).

EXAMPLE 2 Preparation of4-N-acetyl-4-N-(3-acetoxy-propyl)-5-chloro-3(2H)-pyridazinone (III)

Method A

A mixture of 3 g (13.5 mmoles) of4-(3-hydroxypropylamino)-3,5-dichloropyridazine (IV) and 3 g (36.5mmoles) of anhydrous sodium acetate is suspended in 30 cm³ of glacialacetic acid, and the mixture is boiled for 3 hours (TLC ethylacetate:aceton:triethylamine==10:10:0.5). The starting substance(R_(f)=0.48) is used up. The reaction mixture is then cooled, 100 cm³ ofdistilled water are added to it and the mixture is extracted 3 timeswith 50 cm³ each of dichloromethane. The organic phases are combined,dried over magnesium sulfate, filtered with activated coal andevaporated. The crude oily residue is dissolved in 5 cm³ of hotmethanol. Upon cooling4-N-acetyl-4-N-(3-acetoxypropyl)-5-chloro-3(2H)-pyridazinone (III)begins to separate. The separated crystals are filtered and washedsuccessively with cold methanol and ether. Yield: 2.0 9 (51.6%).

Method B

A mixture of 28 g (0.12 mole) of crude compound of the formula (IV) and28 g (0.34 mole) of anhydrous sodium acetate is suspended in 280 cm³ ofglacial acetic acid. The mixture is heated to boiling and the reactionis followed as specified above. The mixture is then cooled, the sodiumacetate is filtered off and washed with glacial acetic acid. The motherliquor is evaporated in vacuo. For the complete removal of the aceticacid 2×50 cm³ of toluene are added to the mixture and it is evaporatedagain. The residue is then dissolved in 100 cm³ of distilled water, theaqueous mother liquor is extracted 3 times with 100 cm³ each ofdichloromethane, dried over magnesium sulfate, filtered over activatedcarbon and evaporated. The residual crude product (29-30 g) is dissolvedin 15-20 cm³ of hot methanol, clarified by activated carbon and filteredwhile hot. The product separates upon cooling. It is filtered and washedsuccessively with cold methanol and cold ether. Yield: 16-20 g (45-50%).

The physical and chemical characteristics of the compound of formula(III) prepared according to any of methods A and B have been foundidentical.

Physical and Chemical Characteristics of the4-N-acetyl-4N-(3-acetoxypropyl)-S-chloro-3(2H)-pyridazinone (III)

M.p.: 108-110° C.

TLC: acetonitrile:methanol=9:1 R_(f)=0.75

Analysis for the formula C₁₁H₁₄ClN₃O₄: C H Cl N Calculated: 45.92% 4.91%12.32% 14.61% Found: 45.63% 5.01 12.36% 14.40% IR (KBr) ν cm⁻¹:3400-2800 [pyridazinone ring (NH—CO)], 1729, 1676 (amides), 1593, 1445,1406, 1362, 1321, 1256, 1205, 1172, 1128, 1099, 1083, 1032, 971, 945,888, 845, 831, 777, 741, 637, 610, 569, 448, 427.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 12.8 [s, (1H) pyridazinone-NH], 7.97 [s,(1H) pyridazinone C-6H], 4.12 [t, (2H) J=6.5 Hz, —CH₂O], {3.8 [m, (1H)and 3.7 [m, (1H), —N—CH₂}, 2.03 [s, (3H), CH₃], 1.97 [s, (3H) CH₃], 1.89[m, (2H), C—CH₂—C].

¹³CNMR (400 MHz CDCl₃) δ ppm: 171.07, 169.68, (acetyl-carbonyl carbonatoms), 159.87 (CO-pyridazinone), 138.2, 138.4, 139.9 (carbon atoms ofthe pyridazinone ring), 62.0 CH₂—O), 44.2 (CH₂—N) , 27.4 (CH₂), 21.7 and20.9 (CH₃ carbon atoms).

The advantage of method B resides in the elimination of the loss ofsubstance during the recrystallization from diethyl ether.

EXAMPLE 3 4-(3-bromopropylamino)-5-chloro-3(2H)-2pyridazinone (II)

30.5 g (0.106 mole) of4-N-acetyl-4-N-(3-acetoxypropyl)-5-chloro-3(2H)-pyridazinone (III) aresuspended in 136 cm³ of 48% aqueous hydrogen bromide solution in a flaskthat may be closed by a Du Pont screw-cap. The reaction mixture is keptat a temperature between 96° C. and 98° C. for 24 hours under stirring[TLC ethyl acetate:acetone:triethylamine=10:10:0.5 (III) R_(f)=0.73].During that time the starting substance is used up. The reaction mixtureis then cooled, the separated crystals are filtered and washed with colddichloromethane. Yield: 27.3 g (95%). The crude product isrecrystallized from 100 to 110 cm³ of isopropanol. Yield: 20.2 g (73%).

Physical and Chemical Characteristics of the4-(3-bromo-propylamino)-5-chloro-3(2H)-pyridazinone

M.p.: 116-118° C.

TLC: ethyl acetate-acetone-triethylamine==10:10:0.5 R_(f)=0.73

Analysis for the formula C₇H₉BrClN₃O₄ (266.53): C H Cl N Calculated:31.55% 3.40% 13.30% 15.77% Found: 31.74% 3.45 13.15% 15.70% IR (KBr) νcm⁻¹: 3183, 2800, 2400, 1545, 1423, 1374, 1324, 1269, 1239, 1214, 1163,1107, 1037, 936, 819, 750, 572.

¹H-NMR (DMSO) δ ppm: 12.45 [s, (1H) NH-pyridazine], 7.65 [s, (1H)-pyridazine], 6.4 [s, (1H) 4NH]), 3.78 [t, (2H), N—CH₂], 3.58 [t, (2H),Br—CH₂], 2.13 [qa, (2H), CH₂].

¹³CNMR (DMSO) δ ppm: 156.93 (Co-pyridazinone), 139.8, 105.9(pyridazinone ring carbon atoms), 34.16 (C—NH), 41.88 (C—Br), 31.95(CH₂).

EXAMPLE 45-chloro-4-{3-[N-[2-(3.4-dimethoxyphenyl)-ethyl]-N-methyl-amino]-propylamino}-3(2H)-pyridazinone(I)

A mixture of 10.66 g (0.04 mole) of4-(3-bromopropylamino)-5-chloro-3(2H)-pyridazinone (II), 10.0 g (0.05mole) of N-methyl-homoveratryl amine (VI) and 8 g of potassium hydrogencarbonate is suspended in 80 cm³ of acetone. The reaction mixture isrefluxed for 8 to 12 hours. The reaction is followed by TLC (eluent:ethyl acetate: acetone:triethylamine==10:10:0.5 (II R_(f)=0.76), (VIR_(f)=0.14), (I R_(f)=0.47)). The mixture is filtered while hot, washedwith acetone and the mother liquor is evaporated in vacuo. To theresidue 50 cm³ of ethyl acetate are added. The possibly separatedinorganic substance is filtered off and the filtrate is evaporatedagain. The residual viscous, oily product (14 to 15 g) is trituratedtwice with 50 cm³ of hot water in order to remove the unreacted startingsubstance of the formula (VI). The warm aqueous solution is decanted.The oily residue is dissolved in methanol and dried over magnesiumsulfate. Upon adding a small amount of diisopropyl ether and cooling themixture white porous substance separates. Thus 9 g (59.0%) of crudeproduct are obtained. M.p.: 89-90° C. After recrystallization fromdiisopropyl ether 7.0 g (46.0%) of the title compound are obtained.

Physical and Chemical Characteristics of the5-chloro-4-{3-[N-[2-(3.4-dimethoxyphenyl)-ethyl]-N-methylamino]-propyl-amino}-3(2H)-pyridazinone

M.p.: 90-92° C.

TLC: ethyl acetate-acetone-triethylamine==10:10:0.5

R_(f)=0.45

Analysis for the formula C₁₈H₂₅ClN₄O₃ (380.88): C H Cl N Calculated:56.76% 6.62% 9.31% 14.71% Found: 56.46% 6.68 9.26% 14.85% IR (KBr) νcm⁻¹: 3290, 3111, 2940, 2860, 2830, 2780, 2700, 1640, 1610, 1570, 1520,1445, 1350, 1260, 1240, 1140, 1100, 950, 900, 800, 600.

¹H-NMR (200 MHz, CDCl₃) δ ppm: 1.67 [s, (1H) pyridazinone-NH], 7.52 [s,(1H) pyridazinone-CH], 6.75 [m, (3H), Ar—H], 6.62 [t, (1H), NH], 3.84and 3.86 [s, (6H), CH₃O], 3.85 [m, (2H), propyl-CH₂], 2.72 and 2.65 [m,(4H) ethyl-CH₂], 2.56 [m, (2H), propyl-CH₂], 2.33 [s, (3H), N—CH₃], 1.80[m, (2H) , propyl-CH₂].

¹³CNMR (200 MHz CDCl₃) δ ppm: 157.69 (pyridazinone C3), 148.46, 146.94,132.64, 120.20, 111.73, 110.93 (CH₃O-phenyl-aromatic carbon atoms),140.41 (pyridazinone C6), 139.85 (pyridazinone C5), 106.8 (pyridazinoneC4), 59.43 (C1-propyl), 55.54 and 55.49 (O—CH₃), 54.83 (C2-ethyl), 42.82(N—CH₃), 41.67 (C3-propyl), 32.87 (CH₂—Ar), 27.66 (C2-propyl).

EXAMPLE 5 Preparation of the Starting Substance

200 g of commercially available 4,5-dichloro-3(2H)-pyridazinone arerefluxed in 1500 cm³ of phosphorus oxychloride for 5 hours. Then theexcess of phosphorus oxychloride is distilled off in vacuo. The residueis poured onto icy water, the crystalline product is filtered and dried.Yield: 200 g (89%) of 3,4,5-trichloro-pyridazine. M.p.: 58-60° C.

What we claim is:
 1. A process for the preparation of5-chloro4-{3-[n-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propylamino}-3(2H)-pyridazinone of the formula (I)

which comprises a1) reacting, in a dipolar aprotic solvent in thepresence of an acid binding agent, a compound of the general formula(II),

wherein X stands for a leaving group, with N-methyl-homoveratryl amineof the formula (VI);

and, if desired, converting the thus obtained compound of formula (I)into an acid addition salt thereof.
 2. A process as claimed in claim 1,wherein said solvent is acetone, acetonitrile, or dimethylformamide andsaid acid binding agent is an alkali carbonate, an alkali hydrogencarbonate or an amine.
 3. A process as claimed in claim 2, wherein theamine is triethylamine or an excess of the reagent of formula (VI).
 4. Acompound of the general formula (II),

wherein X stands for a leaving group.
 5. A compound of the generalformula (II) according to claim 4, wherein X stands for bromine.